Multiple Sclerosis (MS) is one of the most common neurological disorders worldwide and one of the major neurological non-traumatic disability causes in young adults, more common in women than men, the first symptoms appearing around 30 years of age. Multiple sclerosis is a progressive disease, of autoimmune inflammatory origin, characterized by the loss or damage of myelin sheath coating nervous fibers of the Central Nervous System (CNS), which is substituted with connective tissue plaques. This generates an alteration in conduction of nervous impulse and said alteration is the source of the most common symptoms of the disease, such as muscular weakness, spasticity or motor dysfunction, visual alterations, equilibrium problems, urinary dysfunction, constipation, and cognitive or behavioral anomalies (Atlas multiple sclerosis resources in the World. World Health Organization, 2008). The course of the disease is presented with periods of outbreaks alternated with periods of remission of undefined duration. It has been shown that T-lymphocytes play an important role during the beginning and development of the disease. T-lymphocytes are immune system cells responsible of coordination of an adaptive immune response against specific antigens. Normally, during an infection situation of the organism, immune system cells known as antigen-presenting cells, capture and phagocyte the pathogen agent, degrading and exposing its antigens on their surface through the linkage to the Major Histocompatibility Complex (MHC). These cells migrate and move towards T-lymphocytes in lymph nodes or spleen, searching for T-lymphocytes exerting an specific response to the invasive pathogen. This search is made through the interaction between the peptide derived from the pathogen bound to the MHC of the antigen-presenting cell with the T-lymphocyte Receptor (TCR) expressed on the surface of each T-lymphocyte, wherein all TCR have a unique and different specificity for each of the T-lymphocytes. In this manner, when a T-lymphocyte specifically recognizes the pathogenic peptide bound to the MHC, receives positive signals that induce multiplication of this specific T-lymphocyte, in order to generate a suitable number to fight the pathogen. Finally, T-lymphocytes migrate to the infection sites, and, through different mechanisms, achieve the elimination of the infective agent, reestablishing the homeostasis in the organism. Nevertheless, in certain occasions, T-lymphocytes recognize self-antigens, as the case maybe of antigens derived from the myelin sheath from oligodendrocytes, presented in MHC in antigen-presenting cells, generating now an activation of self-reactive T-lymphocytes which will attack specifically the myelin sheath and therefore, initiate the development of MS. Therefore, an effective treatment against this autoimmune disease requires control over activation of self-reactive T-lymphocytes.
Currently, available treatments for MS include drugs with the objective of reducing activity of the disease and modification of its natural course, as well as addressing the symptoms generated by the disease, such as pain, intestinal and urinary problems, sensorial problems, fatigue and others. Among the most common methods of treatment for MS, which have as an objective modifying the course of the disease or its activity, are the treatment with Interferon beta (INF-β), mitoxantrone and glatiramer acetate (Atlas MS resources in the World. WHO 2008). Type 1 Interferon-beta (T1INF-β) is commonly the first election treatment. The mechanism of action of T1INF-β, allowing the reduction of the incidence of outbreaks in MS patients, is not clear. T1INF-β is a native cytokine whose principal function is accentuating the antiviral immunity of T-cells and it has been proposed that T1INF-β stimulates innate immunity conditioning myeloid dendritic cells, a type of antigen-presenting cells, which promote expansion and function of regulatory natural killer T cells (iNKT). Said regulatory iNKT would impede the T-cell effector response in zones where autoimmunity occurs in patients suffering MS. Meanwhile, mitoxatrone is a immunosuppressant drug which was originally used as an antineoplastic agent. Mitoxatrone reduces the number of T-cells, suppresses humoral immunity and produces an inhibition of suppressor T-cells. Mitoxantrone has shown to be useful in reducing the number of outbreaks and progression of incapacity produced by MS (Pericot & Montalban 2003, Neurologia, 18(6):318-323). Glatiramer acetate (also known as copolymer 1), another of treatment methods for MS, is an immunomodulator agent and it has been suggested that it acts by reducing inflammation and promoting oligodendrogenesis and re-myelinization. This suggestion is based on the results obtained in studies performed on an experimental model of autoimmune encefalomyelitis in mice (animal model of MS disease), which show that glatiramer acetate allows an increase in proliferation, differentiation and survival of oligodendrocytes, which relates to an increase of them in damaged sites and thus, allowing in situ reparation processes (Aharoni et al. 2008, PNAS, 105(32): 11358-11363). It has also been proposed that this increase would be triggered by an increase of certain growth factors, such as insulin-like growth factor (IGF-1) and brain derived neurothrophic factor (BDNF) generating a decrease on the symptoms of the disease.
Apart from the three mentioned drugs, other drugs exist used or proposed to be used for the treatment of MS with the objective of modifying the course of the disease. One of them is natalizumab (Tysabri), which is a monoclonal antibody binding to α4 subunit of α4β1 and α4β7 integrins which are expressed, among other places, in the surface of activated T-lymphocytes, avoiding that said T-lymphocytes migrate through the blood-brain barrier to the central nervous system (CNS). Also, natalizumab suppresses in course inflammatory reactions, inhibiting the union of α4 positive leucocytes to osteopontin and fibronectin, which in turns decreases the number of white blood cells in the brain-spinal fluid compared to a non-treated patient. On the other hand, it has been proposed that the use of statins, particularly atorvastatin, which is an agent with cholesterol reducing properties, and which is used in the treatment of cardiovascular diseases, could have a role in suppressing MS. This would be explained since statins, as part of their cholesterol reducing function, would also have the capacity to suppress the activation of T-cells and induction of expression of class II MHC in antigen-presenting cells, thus reducing the immune response. Also, cyclophosphamide has been used as a non-specific immunosuppressant, which has proved to reduce the activity of the disease and the incapacity in a high percentage of patients, without grave side effects.
In spite of the multiple drugs previously described, many MS patients do not respond in a favorable way, either because they have no significant effect on the course of the disease or because they show important side effects. Also, the majority of drugs used up until now, are parenteral drugs, which would imply a higher complexity and discomfort for its application. Therefore, it is necessary to have new treatments modifying the course and progression of the disease and, preferentially, allowing the oral administration of the pharmaceutical composition. Therefore, the objective of our invention is providing a new method for the treatment of MS addressing the abovementioned issues.